The aim of this project is to investigate the transfer of peptides across the skin, specifically the transport pathway of LHRH (luteinizing hormone-releasing hormone) and its analogs. In previous reports we have detailed molecular dynamics studies (using SPASMS) in which energy calculations on LHRH and LHRH agonists/antagonists were used to identify the presence of families of distinct low-energy conformers. Although these compounds exhibit a high degree of flexibility, there appears to be a relatively rigid central tetrapeptide region. Iontophoresis experiments in our laboratory have shown that the delivery of nafarelin (and other analogs) becomes less efficient as the concentration of the peptide in the anodal donor solution is increased. It appears to be able to modulate its delivery by neutralizing the permselectivity of the skin - hence removing the electroosmotic effect which is the principal driving force that facilitates its transfer. We proposed that the introduction of increased hydrophobicity enables the analogs to bind to lipophilic groups present along the delivery pathway. We have used the interactive graphics package MidasPlus to visualize the results and to see that the hydrophobic groups can be oriented so as to present a hydrophobic surface on one side of the molecule, thus providing a site for possible interactions. We have synthesized a three-residue peptide fragment from nafarelin (positions 6-8) that contains the major hydrophobic residues and a conserved arginine residue, in an attempt to localize the source of the interaction with skin. This was found to be as effective as the intact peptide in reducing electroosmosis. We then made a series of three-residue peptides containing specific substitutions that were used to identify the roles of hydrophobicity and charge in determining the ability of a peptide to reverse skin permselectivity and thus modulate peptide transport across skin.